Cells activate genome surveillance pathways, called cell-cycle checkpoints in response to replication perturbation or DNA damage. Central to these surveillance pathways are protein kinases, the upstream kinase, ATR (ataxia telangiectasia mutated and Rad3 related), and its downstream target kinase, Chk1 (checkpoint kinase 1). Complete loss of CHK1 or ATR leads to embryonic lethality in mice. On the other hand, partial loss of these genes, for instance loss of one copy of CHKI or a hypomorphic mutation in ATR, increased genome instability and caused spontaneous cell death even in the absence of extrinsic stress. These findings suggest that these two proteins play key roles in monitoring the DNA replication and in maintaining the genome integrity.